1. Field of Invention
This invention relates to a method for treating urinary tract infections and a composition for use in such method; and more specifically the present invention relates to such method and composition for the treatment of urinary tract infections, specifically urinary tract infections caused by bacteria that produce urease, especially those of the species Proteus, wherein the anti-bacterial effect of methenamine is potentiated or synergized by administering a source of methenamine in combination with a source of hydroxamate groups. In addition, this invention relates to a method of eliminating the pathogenicity of urease producing bacteria by administering to a patient suffering from an infection caused by urease producing bacteria a source of hydroxamate groups. Furthermore, the present invention provides a method of dissolving struvite and apatite urinary stones generally associated with urease producing bacteria by administering a source of hydroxamate groups which provides urine of physiological pH, which due to under-saturation with respect to struvite and apatite crystals can effectively dissolve the associated stones.
2. Description of the Prior Art
The increasing awareness of the importance of urinary tract infections has brought about the realization that adequate drug therapy is required for the treatment of the infection. With this awareness for the need for adequate drug therapy, a corresponding awareness has developed that such adequate drug therapy is difficult to provide.
For example, patients with urinary tract infections often have an associated condition of stasis, stone or obstruction in the urinary tract and the chronicity or recurrence of the urinary tract infections renders unlikely successful treatment. Where such conditions exist and where the infection reoccurs, antibiotics often lose their effect due to the rapid development or acquisition of resistant mutant organisms. Still further, when a patient has a urinary stone, while the infection might be satisfactorily treated initially with a conventional antiobiotic, the stone contains viable bacteria which serve as a source for reinfection. Accordingly, while conventional antibiotics may provide short time relief from urinary tract infections complete cure freuently cannot be achieved through the administration of the conventional antibiotic agent. However, with synthetic anti-bacterial agents, the development of resistance is much less common.
Based upon the effectiveness of synthetic anti-bacterial agents in the treatment of urinary tract infections, methenamine has had a traditional role for some time in this treatment. Methenamine was first synthesized in 1860 and the use of methenamine in the treatment of cystitis was reported as early at 1894. The methenamine exerts its anti-bacterial effect in an acid medium by releasing formaldehyde in a concentration which is bacteriostatic or bactericidal to virtually all known bacteria.
Methenamine, hexamethenamine tetramine, a tertiary amine, has properties of a monoacidic base in its salt formation. As a result different forms of methenamine have been developed and made available as a salt of methenamine and a pharmacologically aceptable organic acid. These forms were developed since they presumably acidify the urine, thereby enhancing the effect of methenamine, which can effectively release the active formaldehyde only in an acid urine. In addition, some anti-bacterial action for the organic acids themselves has been described; however, these agents have proven to be ineffective in acidifying urine in the presence of infection of the urinary tract associated with urea-spliting pathogens. In this respect nearly all species of Proteus and a number of strains of Pseudomonas, Klebsiella, E. Coli and Staphlococcus produce urease, an enzyme which splits the urea according to the following reaction: EQU NH.sub.2 CONH.sub.2 + 2H.sub.2 O urease 2NH.sub.3 + H.sub.2 CO.sub.3 EQU 2NH.sub.3 + H.sub.2 O .fwdarw. NH.sub.4 + OH.sup.-
the hyperammonuria and alkalinity which result through the foregoing reaction appear to be necessary for the precipitation of struvite (MgNH.sub.4 PO.sub.4.6 H.sub.2 O), the predominant component of infected urinary calculi. This alkalinity eliminates the anti-bacterial activity of methenamine and compounds based on methenamine, thereby making these materials ineffective anti-bacterial agents for treatment of infection due to urease producing uropathogens when used in typical anti-bacterial dosages.
Due to the foregoing, where a patient is suffering from a urinary tract infection associated with certain urease producing bacteria, especially species of Proteus, the commonly employed anti-bacterial agent methanamine and compounds based on methenamine are ineffective in the treatment of the infection due to the hyperammonuria and alkalinity which result from the urease producing bacteria. Such alkalinity prevents the conversion of methanamine to its active anti-bacterial from formaldehyde. Based upon the foregoing, the art has long sought a method of treating urinary tract infections and a composition for use in such method which can eliminate the foregoing problem by maintaining physiologic acidity of urine and thereby provide the necessary environment for effective methenamine conversion to formaldehyde, even in the presence of urease producing bacteria.